Prolonging the postcomplex spike pause speeds eyeblink conditioning.

Climbing fiber input to the cerebellum is believed to serve as a teaching signal during associative, cerebellum-dependent forms of motor learning. However, it is not understood how this neural pathway coordinates changes in cerebellar circuitry during learning. Here, we use pharmacological manipulations to prolong the postcomplex spike pause, a component of the climbing fiber signal in Purkinje neurons, and show that these manipulations enhance the rate of learning in classical eyelid conditioning. Our findings elucidate an unappreciated aspect of the climbing fiber teaching signal, and are consistent with a model in which convergent postcomplex spike pauses drive learning-related plasticity in the deep cerebellar nucleus. They also suggest a physiological mechanism that could modulate motor learning rates.

Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance.

BACKGROUND: Schizophrenia is a heritable disorder associated with disrupted neural transmission and dysfunction of brain systems involved in higher cognition. The gene encoding dystrobrevin-binding-protein-1 (dysbindin) is a putative candidate gene associated with cognitive impairments, including memory deficits, in both schizophrenia patients and unaffected individuals. The underlying mechanism is thought to be based in changes in glutamatergic and dopaminergic function within the corticostriatal networks known to be critical for schizophrenia. This hypothesis derives support from studies of mice with a null mutation in the dysbindin gene that exhibit memory dysfunction and excitatory neurotransmission abnormalities in prefrontal and hippocampal networks. At a cellular level, dysbindin is thought to mediate presynaptic glutamatergic transmission. METHODS: We investigated the relationship between glutamate receptor dynamics and memory performance in dysbindin mutant mice. We assessed N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor function in prefrontal cortex pyramidal neurons in vitro with whole-cell recordings, molecular quantitative analyses (reverse transcription-polymerase chain reaction) of the mandatory NMDA receptor subunit NR1, and cognitive function with a spatial working memory task. RESULTS: Decreases in dysbindin are associated with specific decreases in NMDA-evoked currents in prefrontal pyramidal neurons, as well as decreases in NR1 expression. Furthermore, the degree of NR1 expression correlates with spatial working memory performance, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression. CONCLUSIONS: These data show a significant downregulation of NMDA receptors due to dysbindin deficiency and illuminate molecular mechanisms mediating the association between dysbindin insufficiency and cognitive impairments associated with schizophrenia, encouraging study of the dysbindin/NR1 expression association in humans with schizophrenia.

Extinction of a classically conditioned response: red nucleus and interpositus.

It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus. However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction to be an active learning process distinct from acquisition. Accordingly, this current understanding of extinction has guided neural studies that have tried to identify possible brain structures that could support this new learning. However, whether extinction engages the same brain sites necessary for acquisition is not yet clear. This poses an overriding problem for understanding brain mechanisms necessary for extinction because such analysis cannot be done without first identifying brain sites and pathways involved in this phenomenon. Equally elusive is the validity of a behavioral theory of extinction that can account for the properties of extinction. In this study, we looked at the involvement of the interpositus and the red nucleus in extinction. Results show that, although inactivation of both nuclei blocks response expression, only inactivation of the interpositus has a detrimental effect on extinction. Moreover, this detrimental effect was completely removed when inactivation of the interpositus was paired with electrical stimulation of the red nucleus. These findings speak to the important role of cerebellar structures in the extinction of discrete motor responses and provide important insight as to the validity of a particular theory of extinction.

Effects of a corneal anesthetic on extinction of the classically conditioned nictitating membrane response in the rabbit (Oryctolagus cuniculus).

Rabbits (Oryctolagus cuniculus) were presented with 7 daily sessions of tone-alone training after conditioning. Before the beginning of each of the first 4 extinction sessions, an artificial tear solution or tetracaine hydrochloride was administered to the cornea of rabbits in the control group (n = 6) and experimental group (n = 7), respectively. There were no between-group differences in the percentage of conditioned responses between both groups. However, the amplitude of the conditioned response was notably reduced in the tetracaine group (M = 0.40, SEM +/- 0.216) relative to the control group (M = 1.32, SEM +/- 0.639) early in extinction. Results seem to suggest that although motor output has been found to play an important role in extinction, corneal sensory feedback is not necessary.

Brain mechanisms of extinction of the classically conditioned eyeblink response.

It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus (US). However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction as an active learning process distinct from acquisition. Experimental data in eyeblink conditioning suggest that plastic changes specific to extinction may play an important role in this process. Both cerebellar and hippocampal systems may be involved in extinction of these memories. The nature of this phenomenon and identification of the neural substrates necessary for extinction of originally learned responses is the topic of this review.